1. Field of the Invention
The present invention relates to a method for activating an inactive substance at a specific site in a human or other animal.
2. Background of the Invention
The use of antibodies for passive immunization has been utilized for many years. Early attempts using this methodology usually involved the administration of antibodies specific for a disease agent, which were raised in another species and later administered to the recipient which was a member of a different species. This approach proved to be of limited value from the standpoint of effectiveness as well as from the perspective of adverse reactions by the host to the large quantities of foreign antibody protein which had to be administered to achieve significant therapeutic effect. As a consequence, the individual of the species receiving the passively administered antibodies would often develop an adverse reaction to these foreign proteins, resulting in what is commonly known as serum sickness.
Another serious drawback to the early attempts at passive immunotherapy was the poor specificity, or selectivity, of the antibodies that were produced by the source species. Many times the species in which the antibody was produced recognized antigenic determinants and produced antibodies thereto which would react with non-protective determinants on the pathogenic agent in the recipient species or, even worse, would cross-react with the normal tissues of the recipient species. Additionally, because the percentage of antibodies which were therapeutically effective was often quite small compared to the total amount of antibody produced by the source species, and because there was no effective means of separating the useful antibodies from those which were not, the recipient species had to be exposed repeatedly to large quantities of antibody protein in order to receive a protective amount of the useful antibody. Often this repeated exposure of the recipient species to these large quantities of foreign antibody would cause the recipient's own immune system to attack these foreign proteins, resulting in greatly decreased therapeutic effectiveness and serum sickness. As a result of these complications, the use of passive immunotherapy in the past has been extremely limited.
In recent years, interest in the use of passive immunotherapy has been restimulated by the development of monoclonal antibody technology. Because of the nature of this technology, it is now possible to produce antibodies to substances which in the past were not sufficiently immunogenic for purposes of polyclonal antibody production and actually select the antibody that has the desired therapeutic specificity. In addition, since these antibodies are produced by a single clone responding to stimulation by a single epitopic determinant, the high degree of site specific selectivity that can be achieved makes it conceivable that much lower concentrations of passively administered antibody may now be used.
Early clinical investigators quickly realized the advantages of this technology and endeavored to utilize monoclonal antibodies which were specific for the site of disease in the host, but would not cross-react with normal host tissue. This great specificity, in turn, enabled scientists to couple monoclonal antibodies to highly toxic drugs or radioactive substances which in the past could not effectively be utilized because of the toxic side effects to the host when the substances were administered systemically. However, a potential danger inherent in this approach to passive immunotherapy using monoclonal antibodies coupled to an active toxic substance, is that these active substances may become uncoupled from the monoclonal antibody and thus pose a toxic threat to the host. The method according to the present invention circumvents these earlier problems by coupling a relatively non-toxic substance, the activator, to an antibody specific for the target site.
Although in many instances highly effective drugs have been developed for treatment of various disease states, their toxic side effects at concentrations necessary to achieve therapeutic effectiveness often negates their usefulness.
One specific problem of lack of selectivity relates, for example, to thrombolytic agents used to dissolve blood clots.
Coronary arteriographic studies indicate that 90-95% of transmural myocardial infarctions are caused by coronary thrombosis (DeWood, M. A. et al., N. Eng. J. Med., 303:897-902 (1983)). Although thrombolytic agents currently available can lyse coronary artery thrombi in the early hours of coronary thrombosis and thereby diminish myocardial injury, their clinical application has been attended by significant problems. These agents are activators of the precursor plasminogen which is activated to the fibrinolytic enzyme plasmin. Plasmin is non-selective and not only effects lysis of the fibrin in the thrombus, but also promotes generalized fibrinogenolysis, at times resulting in severe bleeding (Laffel, G. L. et al., ibid, 311:710-717 and 770-776 (1984)). Human tissue plasminogen activator may be more fibrin-specific, but bleeding complications have nevertheless been observed.
Currently, two activators are commercially available, streptokinase and urokinase. Both are indicated for the treatment of acute cardiovascular disease such as infarct, stroke, pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion, and other venous thromboses. Collectively, these diseases account for major health hazards and risks. Streptokinase and urokinase, however, have severe limitations. Neither has a high affinity for fibrin; consequently, both activate circulating and fibrin-bound plasminogen relatively indiscriminately. In addition, the plasmin formed in circulating blood is neutralized rather quickly and its efficacy lost for useful thrombolyses. Residual plasmin will degrade several clotting factor proteins, for example, fibrinogen, factor V and factor VIII, causing hemorrhagic potential. In addition, streptokinase is strongly antigenic and patients with high antibody titers respond inefficiently to treatment and cannot remain on continuous treatment. The recent availability of human tissue-type plasminogen activator has somewhat improved the therapeutic prospects. Nevertheless, the issue of selectivity remains an important one.